The lymphatic system is crucial for the maintainance of good health and for the prevention and cure of disease. Congenital hypoplasia and failed regeneration of lymphatic tissue result in lymphedema. Primary lymphedema appears at birth (Milroy disease) or, more commonly, after puberty (Meige disease). Although lymphedema was first described more than a century ago, little progress has been made in understanding the mechanisms that cause it. Furthermore, little progress has been made in identifying the players that participate in the normal development of the lymphatic vasculature. Investigation of the normal development of the lymphatic system has been hindered by the lack of known lymphatic-specific markers. Consequently, hypotheses about the origin of the lymphatic vessels are still controversial. The most widely accepted view, which was proposed by F. Sabin in 1902, is that isolated primitive lymph sacs bud from the endothelium of veins during early development; from these primary lymph sacs, the peripheral lymphatic system spreads by endothelial sprouting into tissues where local capillaries form. This grant proposal is based in our identification of the homeobox gene Proxl as the first specific marker of lymphatic endothelial cells. Functional inactivation of Proxl in mice leads to phenotypic alterations in lymphatic vasculature and, ultimately, to embryo death. Detailed analyses of Proxl-null and Proxl heterozygous mice have indicated that lymphangiogenesis requires activity of Proxl in a subpopulation of endothelial cells in embryonic veins. Proxl-null mice are devoid of lymphatic vasculature. Proxl activity also determines the final lymphatic fate of budding endothelial cells. The elucidation of the molecular mechanisms by which Proxl participates in the formation of the lymphatic vasculature and the identification of other novel molecules that participates in this process will increase our understanding of normal lymphangiogenesis, and therefore, advance the treatment and prevention of disorders of the lymphatic system.